Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
  • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
  • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
  • C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
  • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
  • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
  • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
  • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• United States Patents Nos. 3,150,136 and 3,167,537 disclose, inter alia,certain pyrazoloquinazolone carboxylic acids whcih are useful as intermediates for the preparation of dyestuffs.
• German Patent No. 1,111,505 discloses substituted 2-carboxy-pyrazolo-[5,1-b] quinazolin-9(4H)-ones which are useful as photographic colour developers.
• the references do not disclose or suggest any pharmaceutical utility for these acids, nor do they disclose the corresponding tetrazole or carboxamidotetrazole derivatives.
• Preferred compounds are those having a compound having the following formula I: wherein X is hydrogen, hydroxy, methyl, methoxy, chlorine, fluorine or another halogen, or trifluoromethyl; R 1 is hydrogen, methyl or ethyl; Y is hydrogen or methoxy; Z is -COOH, and R 1 is hydrogen, methyl or ethyl; with the proviso that, when R is hydrogen and Z is X is hydrogen, methyl, methoxyk, chlorine, fluorine, triiluoromethyl or hydroxy and Y is hydrogen or, when X is methoxy, is methoxy; or with the proviso that, when R 1 is methyl or ethyl and Z is Y is hydrogen and X is hydrogen, methyl, methoxy or halogen; or with the proviso that, when Z is R is hydrogen or methyl, X is hydrogen, methyl, methoxy, hydroxy, or chlorine, and Y is hydrogen or, when R 1 is methoxy, is me
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising an anti-allergic effective amount of a compound of the formula I: wherein X is hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, halogen, trifluoromethyl, or SO n R wherein R is alkyl having from 1 to 6 carbon atoms, and n is 0,1 or 2; Y is hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, or 2-tetrahydrothienyl; R 1 is hydrogen or alkyl having from 1 to 6 carbon atoms; Z is COOH, or a pharmaceutically acceptable salt thereof: and a diluent or carrier for that compound or salt thereof.
• X is hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, halogen, trifluoromethyl, or SO
• the present invention provides a method of preventing the allergic response in a mammal which comprises administering to said mal an anti-allergic effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
• the present invention also provides a compound of the formula II: wherein R 2 is alkyl of from 1 to 6 carbon atoms.
• the tetrazoles of the present invention may be prepared from the corresponding acids or esters by methods familiar to those skilled in the art.
• the properly substituted carboxylic acid may be converted to the corresponding acid halide such as the chloride by treatment with thionyl chloride or oxalyl chloride and converted to the acid amide by treatment with ammonia.
• the amide is dehydrated by treatment with, for example, phosphorous oxychloride or thionyl chloride in dimethylformamide thereby producing the corresponding nitrile which when treated with sodium azide and ammonium chloride, for example, will yield the corresponding tetrazole.
• the above-described amides may also be prepared directly from the corresponding esters by treatment with, for example, gaseous ammonia by methods familiar to those skilled in the art.
• the carboxamido tetrazoles of the invention i.e., compounds of the formula I wherein Z is . and X, Y and R 4 are as defined above may be prepared from the corresponding carboxylic acids by methods familiar to those skilled in the art.
• the properly substituted carboxylic acid may be converted to the corresponding acid halide such as the chloride by treatment with thionyl chloride or oxalyl chloride.
• Treatment of the halide with 5-aminotetrazole produces the carboxamido tetrazoles of formula I.
• a carboxylic acid may be treated with 1,1-carbonyl- diimidazole to produce a compound of formula III.
• Treating the so produced compound of formula III with 5-aminotetrazole, for example in dimethylformamide solution, will produce the corresponding carbox - amidotetrazole of formula I.
• the intermediate carbonylimidazole of formula III need not be isolated prior to being treated with 5-aminotetrazole.
• the properly substituted carboxylic acid may be directly coupled with 5-aminotetrazole by use of such agents as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroguinoline (EEDQ), dicyclohexylcarbodiimide (DCC) and the like.
• the 3-alkoxycarbonyl-2-pyrazolin-5-ones of formula IV may be prepared by the procedure of R.V. Rothenberg, J. Prakt. Chem., 2, 53 (1895).
• the substituted N-alkyl isatoic anhydrides of formula V may be prepared by the procedure of G.E. Hardtmann, et al., J. Hetero. Chem., 12, 565 (1975); these compounds may also be prepared by alkylating the corresponding N-unsubstituted isatoic anhydride which themselves may be prepared for example, by reacting a properly substituted anthranilic acid with phosgene, as described below. Several of these compounds are also commercially available from the Aldrich Chemical Company, Milwaukee, Wisconsin and the Sherwin Williams Company, Cleveland, Ohio.
• the isatoic anhydride is then converted to a 2-aminobenzoic acid hydrazide of the formula by treatment with, for example, an aqueous hydrazine hydrate solution.
• the hydrazide is next converted to the desired 2-carboxypyrazolo[5,1-b]quinazolin-9(4H)-ones by treatment with a dialkyl oxalacetate, preferably diethyl oxalacetate sodium salt, for example, in aqueous solution.
• the thioalkyl anthranilic acids of formula II which are utilized to prepare the corresponding thioalkyl substituted isatoic anhydrides are novel, and may themselves be prepared by alternate procedures which are considered equivalent for purposes of the invention.
• One such procedure involves the steps of treating a halo-substituted 2-nitrobenzoic acid with sodium sulfide; alkylating the so produced mercaptan; followed by reduction of the nitro group thereby producing the desired thioalkyl substituted anthranilic acid II.
• the above-described alkylated mercaptan may also be produced by treating the halo-substituted 2-nitrobenzoic acid with a mercaptide such as a sodium mercaptide.
• the starting halo-substituted 2-nitrobenzoic acids are either commercially available or may be prepared by methods known to those skilled in the art.
• 5-chloro - 2-nitrobenzoic acid is available from Aldrich Chemical Company, Milwaukee, Wisconsin 53233.
• the preferred thioalkyl anthranilic acids are represented by the following formula: J. Pharm. Soc. Japan, 72, 76 (1952), [C.A.: 46, 11150h (1952)] discloses ethyl 5-thioethylanthranilate.
• a compound of the formula VII wherein X, Y and Z are as defined above may be N-alkylated by standard procedures to produce the corresponding N-alkyl derivative.
• the compounds of the invention of formula I are acids or are acidic in nature and form pharmaceutically acceptable salts with both organic and inorganic bases such as dimethylaminoethanol, the alkali metal and alkaline earth hydroxides and the alkali metal carbonates and bicarbonates such as lithium, sodium, potassium and calcium hydroxide, and the carbonates and bicarbonates of lithium, sodium and potassium.
• the salts are prepared by reacting an acid or the tetrazole with the desired base in the conventional manner.
• the tetrazoles and acids differ from their respective salts somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective tetrazoles or acids for purposes of the invention.
• the compounds'of the invention can exist in unsolvated as well as solvated forms, including hydrated forms.
• the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
• the thioalkyl groups, alkoxy groups and alkyl groups contemplated by the invention comprise both straight and branched carbon chains of from 1 to 6 carbon atoms.
• Representative of such groups are methyl, ethyl, isopropyl, pentyl, 3-methylpentyl, methcxy, ethoxy, propoxy, 1-ethylbutoxy, pentoxy, methylthio, isopropylthio, n-butylthio and the like.
• halo is intended to include fluorine, chlorine, bromine and iodine.
• the compounds of the invention of formula I are new chemical substances of value as pharmacological agents which prevent the allergic response in mammals by inhibition of the release of such allergic mediators, as histamine.
• the assay by which this utility was established is carried out as follows.
• PCA Rat Reaginic Passive Cutaneous Anaphylaxis
• the PCA test (D.J. Herzig, P.R. Schumann, E.J. Kusner, L. Robichaud, R.E. Giles, B. Dubnick, M. von Strandt - mann, S. Klutchko, M. Cohen, and J. Shavel, Jr., "Immunopharmacology", M.E. Rosenthale and H.C. Mansmann, Eds., Spectrum Publications, Inc., New York, N.Y., 1975, pp. 103-124) involved immunization of rats with 1 mg of. ovalbumin intramuscularly and approximately 10 10 B.
• pertussis organisms as pertussis vaccine, intraperitoneally.
• the rats were bled and the serum was prepared: Suitable dilutions of antiserum were injected intradermally at various sites on the back of rats 48 hrs before an intravenous injection of 1 mg of ovalbumin in 1 ml of physiological saline and 0.25% Evans Blue.
• the animals were killed in ether, the dorsal skin was reflected, and the mean orthogonal diameter of the wheal was measured.
• the drugs were suspended in 1% gum tragacanth in physiological saline and given 10-15 min before intravenous antigen challenge.
• the compounds were dissolved in the saline/ovalbumin/Evans Blue solution and given with the antigen. If necessary, the compounds were first dissolved in a slight molar excess of sodium bicarbonate and then diluted into the antigen solution. Groups of five animals were used for all dose levels and control groups.
• Test results obtained for several preferred compounds of the invention are as follows: 7-methoxy-2(lH-tetrazol-5-yl)-pyrazolo[5,1-b]quinazolin-9-(4H)-one shows a 100% inhibition of allergic response when administered intraperitoneally to the rat at a dose of 5 mg/kg; 4,9-dihydro-6,7-dimethoxy-9- oxopyrazolo[5,1-b]quinazoline-2-carboxylic acid shows a 100% inhibition of the allergic response when administered intravenously to the rat at a dose of 0.1 mg/kg; 4,9-dihydro-7-fluoro-9-oxopyrazolo[5,1-b]-quinazoline-2-carboxylic acid shows a 62% inhibition of the allergic response when administered intravenously to the rat at a dose of 0.1 mg/kg; 4,9-dihydro-7-(methylsulfinyl)-9-oxo-pyrazolo-
• compositions of the invention can be administered in a variety of dosage forms such as tablets or capsules and liquids for oral or parenteral use.
• dosage forms may contain, in addition to the active component, any of the usual compounding excipients such as flavors, colors, stabilizers and tableting materials such as binders, fillers, lubricants and the like.
• the dosage requirements may vary with the particular composition being employed and may depend- on the severity of the symptoms being presented and the size of the mammal being treated. In general, an amount of from about 0.1 to about 10 mg/kg of the active component in single or divided doses will be sufficient to accomplish the method of the invention.
• the product obtained is 6,7-dimethoxy-2-(1H-tetrazol-5-yl)-pyrazolo[5,1-b]-quinazolin-9(4H)-one.
• the products obtained are the 7-fluoro- and 8-trifluoromethyl-2-(lH-tetrazol-5-yl)-pyrazolo[5,1-b]quinazolin-9(4H)-ones.
• the sodium salt of the 5-methoxy compound of Example 11 As the free tetrazole is dissolved with warming in an equivalent amount of 0.1N aqueous sodium hydroxide solution, the water is evaported off and the sodium salt is dried under vacuum.
• the potassium, calcium and magnesium salts are prepared in the same manner.
• a solution of methyl anthranilate (75.5 g; 0.5 mole) in CH 2 Cl 2 (1.0 1) is cooled to -70° and a solution of tert-butyl hypochlorite (54 g; 0.5 mole) in CH 2 Cl 2 (150 ml) is added slowly keeping the temperature @ -70°.
• the resultant N-chloroanthranilate solution is stirred for 1.0 hr and then tetrahydrothiophene (110 ml) is added at such a rate as to maintain the exotherm to less than 10°.
• the dark solution is stirred @ -70° for 2.0 hr, triethylamine (125 ml) is added dropwise, and the solution is stirred for 24 hrs.
• a mixture of 2.25 g of 4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carbonitrile, 1.9 g of sodium azide, 1.5 g of ammonium chloride and 350 ml of dimethylformamide is stirred and heated at 100°C for 20 hours, then evaporated at reduced pressure.
• the residue is stirred with 1 liter of diluted hydrochloric acid and the resulting solid is collected by filtration.
• the solid is stirred with excess saturated aqueous sodium carbonate and the solution is clarified by filtration.
• a sample of the above tetrazole is dissolved in an aqueous solution of one equivalent of sodium hydroxide.
• the solution is clarified by filtration and freeze-dried to give a residue of the sodium salt.
• potassium hydroxide, calcium hydroxide or magnesium hydroxide for sodium hydroxide, one can obtain the potassium, calcium or magnesium salt, respectively.
• a mixture of 3.5 g of 7-chloro-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carbonitrilb, 2.5 g of sodium azide, 2.1 g of ammonium chloride and 600 ml of dimethylformamide is stirred and heated at 100°C for 18 hours, then evaporated at reduced pressure, removing about 575 ml of solvent.
• the residue is poured into excess dilute hydrochloric acid and the resulting solid is collected by filtration and washed with water.
• the solid is stirred with excess aqueous sodium carbonate and the solution is clarified by filtration.
• a mixture of 3.0 g of 7-fluoro-4,9-dihydro-4-methyl-9-oxo-pyrazolo-2-carbonitrile and 500 ml of dimethylformamide is stirred and heated at 100°C for 2 hours, then treated with 1.9 g of ammonium chloride and 2.3 g of sodium azide, and stirred and heated at 100°C for an additional 18 hours.
• the mixture is cooled, poured into 2.5 liters of ice water and acidified to pH 2 with concentrated hydrochloric acid.
• a mixture of 2.5 g of 4,9-dihydro-7-methoxy-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carbonitrile, 1.9 g of sodium azide, 1.5 g of ammonium chloride and 400 ml of dimethylformamide is stirred and heated at 100°C for 22 hours, then evaporated at reduced pressure
• the residue is stirred with 100 ml of tetrahydrofuran and the mixture is diluted with 1 liter of ice water.
• the resulting solid is collected by filtration, washed with water and dissolved in 300 ml of 0.5 N aqueous sodium hydroxide.
• the solution is clarified by filtration and the filtrate is acidified with concentrated hydrochloric acid.
• a stirred suspension of 5.3 g of a 50% mineral oil dispersion of sodium hydride in 30 ml of dimethylformamide is treated dropwise at -10°C, under a nitrogen atmosphere, with a solution of 15.6 g of 5-oxo-2-pyrazoline-3-carboxylic acid, ethyl ester, in 65 ml of dimethylformamide. After the evolution of hydrogen ceases, the mixture is stirred for 2 hours while allowing the temperature to rise to +10°C.
• the mixture is recooled to -10°C and treated dropwise, with stirring, with a solution of 21.6 g of 90% N-methylisatoic anhydride in 150 ml of dimethylformamide, then stirred for 18 hours while allowing the temperature to rise to 20-25°C.
• the mixture is heated at 90°C for 1 hour, cooled and poured into 3 liters of ice water containing 10 ml of concentrated hydrochloric acid (final pH about 5).
• the resulting precipitate is collected by filtration and the filtrate is extracted several times with 600 ml portions of dichloromethane.
• the precipitate is dissolved in 1 liter of dichloromethane and the solution is combined with the above dichloromethane extracts.
• the sodium salt is prepared by mixing the product with an equivalent amount of 0.1N aqueous sodium hydroxide solution with warming to cause the product to dissolve, evaporating the water off and drying the sodium salt product in vacuum.
• the potassium, calcium and magnesium salts are prepared by the same procedure.
• 1,1'-carbonyldiimidazole (1.46 g; 9.0 mmole) is added to a warm (90°) suspension of 4,9-dihydro-7-methyltnio-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (1.1 g; 4 mmole) in DMF (40 ml) 5-amino-1H tetrazole monohydrate (0.46 g; 4.5 mmole) is added and the solution is heated @ 90° for 3.5 hrs. The product crystallizes out on cooling. Yield 0.5 g; mp 285° (d).
• the substituted isatoic anhydride (0.14 mole) is slowly added to a cold (+5°C to +10°C) 18% aqueous solution of hydrazine (225 ml). During the exothermic reaction a white solid is formed. After stirring at room temperature overnight, the product is filtered off and washed with water. The hydrazide is used as is or is purified via crystallization before use.
• 6-methylthio-2H-3,1-benzoxazine-2,4-(1H)-dione 25.11 g; 0.72 mole is added to a cold solution of 54.4% hydrazine (75 ml) in water (75 ml). After stirring at room temperature overnight, the white solid is filtered, washed with cold water and dried. Yield 21.3 g; mp 124-127°.
• a solution of 26.6 g of 5-methylisatoic anhydride in 150 ml of dimethylformamide is treated with 17.5 g of anhydrous sodium carbonate, then with 32 g of iodomethane, and the mixture is stirred at 20-25°C for 18 hrs.
• the reaction mixture is poured into 1.25 liter of ice water and the resulting precipitate of N,5-dimethylisatoic anhydride is collected by filtration, washed with water and dried; mp 166-169°C.

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• 1980
  • 1980-01-23 DE DE8080300216T patent/DE3065963D1/de not_active Expired
  • 1980-01-23 EP EP19800300216 patent/EP0015065B1/de not_active Expired

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